Apoptosis indicates a phenomenon resulting in the death of unnecessary cells or dangerous cells themselves, which is for life conservation of an individual. In Greek, apoptosis means “to fall.” It describes the falling of cell organisms, and was named by comparing the process of cell death to the falling of petals from a flower, which was first observed in 1972 by Kerr, et al (Kerr et al., Br J Cancer, 1972, 26:239-257). Apoptosis plays an important role in physiological events, including cell development, cell differentiation, cellular immunity and the like (Meier et al., Nature, 2000, 407:796-801). Meanwhile, in various pathologic conditions and diseases, apoptosis is important. For example, in neurodegenerative brain diseases such as Alzheimer's disease and Parkinson's disease, due to accumulation of beta amyloid, etc., nerve cells are damaged, thereby increasing apoptosis (Thomson, Science, 1995). As another example, when a successful treatment was performed by an antitumor agent, a large amount of apoptosis is generated in tumor tissues (Thomson, Science, 1995, 267:1456-1462). On the other hand, the reduction of apoptosis is involved in the generation of a tumor. Also, in a stroke and myocardial infarction, due to a lack of blood in the brain and heart, brain cells and myocardium cells are damaged, respectively, resulting in apoptosis (Du et al, J Cereb Blood Flow Metab, 1996, 16:195-201; Narula et al., New Engl J Med, 1996, 335:1182-1189). Also, in diseases such as organ transplantation rejection, autoimmune disease, arteriosclerosis and virus infection, apoptosis frequently occurs (Thomson, Science, 1995, 267:1456-1462; Kageyama et al., Ann Thorac Surg, 1998, 65:1604-1609).
Such apoptosis is very important in clinical diagnosis and treatment. In other words, imaging of apoptosis may be of great help in early diagnosis and progression monitoring of neurodegenerative brain diseases (Alzheimer's disease, Parkinson's disease, etc.), monitoring of disease progression in myocardial infarction and stroke, monitoring of cancer therapeutic effect following antitumor drug treatment, determination on possibility of rupture of atheromatous plaques in arteriosclerosis, or the like, related to excessively increased apoptosis. Also, a selective delivery of a therapeutic or protecting agent to apoptotic cells may significantly improve a therapeutic effect while reducing side effects.
One of the early events occurring in apoptotic cells is the change of the distribution of phospholipids that constitute the cell membrane. The most characteristic thing among them is the exposure of phosphatidylserine to the outside of the cell membrane. Normally, phosphatidylserine is kept inside the cell membrane, but when a cell receives an apoptotic signal or when a red blood cell is aged, it is exposed to the outside of the cell membrane (Fadeel, B. et al., Cell Mol Life Sci, 2003, 60:2575-2585). A macrophage recognizes the exposed phosphatidylserine through a receptor on the cell surface and phagocytoses the apoptotic cell (Fadok, V. A. et al., J immunol 1992, 148:2207-2216; Fadok, V. A. et al., Nature 2000, 405:85-90; Park, S. Y. et. al., Cell Death Differ, 2008, 15:192-201). Especially, a large number of tumor cells show an increase of expression of phosphatidylserine outside the cell membrane (Utsugi, T. et al., Cancer Res. 1991, 15:3062-3066; Ran, S. et al., Cancer Res. 2002, 62:6132-6140; Woehlecke, H. et al., Biochem J. 2003, 376:489-495). Also, the vascular endothelial cells of a small vessel in a tumor tissue expose phosphatidylserine outside of the cell membrane (Ran, S. et al., Cancer Res. 2002, 62:6132-6140; Zwaal, R. F. A. et al., Blood. 1997, 89:1121-1132). Accordingly, due to such roles of phosphatidylserine, in various situations especially including tumors, the phosphatidylserine is deemed as a target substance for diagnosis, treatment, and treatment monitoring.
At present, the protein annexin V is generally used to detect phosphatidylserine on the surface of apoptotic cells. It is a protein having a molecular weight of 36 kDa, and binds to phosphatidylserine with strong affinity (Vermes, I. et al., Immunol Methods. 1995, 184:39-51). Meanwhile, although annexin V is a very useful target substance or probe for in vitro application, its in vivo application is reported to be restricted because of, for example, slow removal out of the body due to its large molecular weight (Vermeersch, H., et al., Nucl Med Commun. 2004, 25:259-263; Belhocine, T. Z. et al., J Proteome Res. 2004, 3:345-349).
Meanwhile, in the case of Alzheimer's disease, PIB (Pittsburgh Compound B, N-methyl 2-(4′-methylaminophenyl-6-hydroxybenzathiazole) is currently used for nuclear medicine imaging or monitoring, with label of radioisotope [11C], because it is combined with beta amyloid protein within Alzheimer's disease-affected tissues. However, whether the accumulation of amyloid exactly reflects nerve injury or apoptosis, and a patient's clinical symptoms is still argued, and not clear. Further, there is a report that [11C]-PIB is not a specific imaging probe of Alzheimer's disease, but a non-specific imaging probe of cerebral amyloidosis (beta amyloid-related cerebral amyloidosis) Related to beta amyloid (Lockhart et al., Brain. 2007, 130:2607-2615). In consideration of these views, in a neurodegenerative brain disease such as Alzheimer's disease, it is required to develop a technology for grasping the exact degree of disease progression by directly detecting or diagnosing apoptosis.
Blood-brain barrier (BBB) is a structure having a tight junction between cerebrovascular endothelial cells, and astrocytes strengthening the junction, and inhibits a substance within a blood vessel from passing through a blood vessel wall and reaching the inside of brain parenchyma. For this reason, many drugs developed as brain disease therapeutic agents have a problem in that they cannot easily pass through the blood-brain barrier. Also, materials capable of detecting or targeting apoptosis have a problem in that they cannot easily pass through the blood-brain barrier. At present, the development of a carrier capable of delivering a drug by passing through a blood-brain barrier has been actively conducted. Meanwhile, a peptide having a specific amino acid sequence has a function of delivering a drug or siRNA by passing through a blood-brain barrier (Kumar et al., Nature. 2007, 448:39-43; Teixido and Giralt, Journal of peptide science. 2008, 14:163-173).
Theranosis (theragnosis, theragnostics) is a compound word of therapy with diagnosis (diagnostics), which indicates a therapy technique combined with a diagnosis technique. In such a case, a response in a therapeutic agent for each patient may be determined and applied to selection of a therapeutic method. This may prevent misuse or abuse of drugs, and highly distribute to improvement of a therapeutic effect. (Frederic P et al., Crit. Care Med, 2009, Vol. 37, No. 1(Suppl.) S50-S58; Haglund E et al. Annals of Biomedical Engineering, Vol. 37, No. 10, 2009, pp. 2048.2063; Ozdemir V et al., Nature Biotechnology, Vol. 24, No. 8, 2006, 942-946)